ACC: Treating Pre-Hypertension Reduces Hypertension Risk Modestly

Action Points

Inform interested patients that this study suggested that treating people with systolic pressures between 120 and 140 mm Hg with the antihypertensive agent Atacand (candesartan) for two years may reduce or delay the risk of subsequent hypertension by about 15% several years later.

Among pre-hypertensive patients in the TROPHY trial who were assigned to Atacand or placebo for two years, followed by two years of placebo for all, Atacand pre-treatment reduced the risk of stage I hypertension by 15.6%, reported Stevo Julius, M.D., of the University of Michigan, and colleagues, at the American College of Cardiology meeting.

Pre-treatment also reduced the risk of serious adverse events compared with placebo, they said.

But a cardiologist who was not involved in the study commented that while the concept of early intervention to prevent hypertension is sound, the results of the trial are "underwhelming." "It's not as impressive as I originally thought," said James H. Stein, M.D., of the University of Wisconsin.

"What this shows is that if you treat people's blood pressure before they reach a threshold, they don't reach that threshold," Dr. Stein added. "No surprise, because you're already treating them for the disease that you're trying to prevent. Remember, the disease is defined by a number, and if you treat them before they're below that number, they're not going to get to that number."

The TROPHY (Trial of Preventing Hypertension) investigators enrolled patients who had repeated measurements of systolic pressures from 130 to 139 mm Hg, and diastolic pressures of 89 mm Hg or lower, or systolic pressures of 139 mm Hg or lower with diastolic pressures between 85 and 89 mm.

The mean systolic pressure in the study patients was about 134 mm Hg. Mean diastolic pressure was about 84.5 mm Hg.

Following a three-week run-in period in which blood pressures were recorded weekly with an automatic device (to ensure uniform readings) the participants were randomly assigned in a double-blind fashion to two years of Atacand or placebo, followed by the two years of placebo for all. During the all-placebo phase, investigators remained blinded to each patient's initial treatment assignment.

When the study participant reached the endpoint of stage 1 hypertension, they were started on antihypertensive agents, including Toprol XL (metoprolol) at 50 mg daily, Microzide (hydrochlorothiazide) at 12.5 mg daily, or other therapies at the discretion of the treating physician, with the exception of angiotensin-receptor blockers,

Patients in both the Atacand and placebo groups were instructed to make diet, exercise, and other changes in their lifestyle to reduce blood pressure throughout the trial.

A total of 409 patients were assigned to Atacand, and 400 were assigned to placebo. Data on 391 patients on the active drug and 381 in the placebo group were available for the analysis. The mean patient age was 48.5 years, and 60% were men.

The investigators found that during the first two years of the trial, 154 patients on placebo (40.4%) developed hypertension, compared with 53 (13.6%) in the Atacand group. The relative risk reduction for treatment compared with placebo during this phase was 0.34, 95% confidence interval, 0.25-0.44, P<0.001.

But by the four-year visit, when all patients had been on placebo for two more years, the differences between the groups narrowed. At study end, 240 participants (63%) in the placebo group, and 208 in the Atacand group (53.2%) had progressed to stage 1 hypertension. At this point the relative risk for treatment over placebo was 0.84, 95% CI, (0.75-0.95, P=0.007).

Serious adverse events occurred in 3.5% of the participants assigned to Atacand, and 5.9% of those receiving placebo. The investigators did not provide P values or relative risk ratios for the differences in adverse events.

"Over a period of four years, stage 1 hypertension developed in nearly two thirds of patients with untreated pre-hypertension (the placebo group)," the TROPHY investigators concluded. "Treatment of pre-hypertension with candesartan appeared to be well tolerated and reduced the risk of incident hypertension during the study period. Thus, treatment of pre-hypertension appears to be feasible."

Dr. Stein commented, "What would have been most interesting was if the people on candesartan who got put back on placebo at the end of year two, remained flat [on a data plot]. But what you can clearly see is that once the candesartan people went off placebo they started to go straight back up, and although at the end of the trial there's a statistically significant difference here, it's relatively small."

Dr. Stein added the trial may have had lukewarm results because the intervention was started too late.

"We know that people with systolic blood pressures in the range of 120 to 140 mm Hg are already abnormal and have abnormal arterial responses to that, even at as young an age as 48 years," he said.

The seventh report of the Joint National Committee (JNC 7) proposed a definition of pre-hypertension as systolic pressure 120 to 139 mm Hg or diastolic 80 to 89 mm Hg. It recommended that patients with pre-hypertension who do not have diabetes, chronic renal failure, end-organ damage, or clinical evidence of cardiovascular disease should generally be treated with nonpharmacologic therapies such as weight reduction, sodium restriction, increased physical activity, and avoidance of excessive alcohol.

Reviewed by Zalman S. Agus, MD Emeritus Professor at the University of Pennsylvania School of Medicine

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